DESCRIPTION: The envelope protein (env) of HIV-1 plays two critical roles in the initial stages of virus infection: it binds virus to the cell surface by a high affinity interaction with CD4, and undergoes a conformational change that leads to fusion between the viral envelope and a cellular membrane. While env-CD4 interactions have been well characterized, the mechanisms controlling the subsequent membrane fusion reaction are poorly understood. It is clear, for example, that binding to CD4 alone does not lead to membrane fusion. CD4 expressed in nonhuman cells is not sufficient for virus infection due to a block in entry, and different HIV-1, HIV-2, and SIV strains can exhibit marked cellular tropism: while some virus strains preferentially infect T-cells, others infect macrophages and some infect both of these CD4-positive cell types. These and other findings have shown that in addition to CD4 one or more cell-specific co-factors are required for HIV-1 entry. While a number of molecules have been proposed to serve as HIV-1 co-factors, none have proven to be required for either virus infection or syncytia formation. Very recently, a seven transmembrane domain protein has been found to serve as a co-factor for T-cell tropic HIV-1 strains. The molecule, termed Fusin, is related to the chemokine receptor families. The investigator has found that introduction of both Fusin and human CD4 into many different nonhuman cell lines renders them permissive for T-tropic env mediated cell-cell fusion and for virus infection. Furthermore, preliminary studies showed that env-CD4 complexes interact directly with Fusin, whereas env alone binds weakly. The data suggest that Fusin also serves as a alternate receptor in models of CD4-independent infection by HIV-2. Identification of this and related molecules represents an exciting opportunity to study virus tropism and entry at the molecular level.The proposal has 4 specific aims 1) Characterize the role Fusin plays in the entry and fusion activity of different HIV-1 strains; 2) Examine the extent to which chemokine receptors and related molecules can serve as co-factors for T-and M-tropic HIV-1 strains as well as for HIV-2 and for SIV; 3) Explore the interactions between env, CD4, and Fusin or related molecules; identify the regions in env that participate in these interactions; and investigate whether these interactions lead to conformational changes in env that may lead to membrane fusion; and 4) Extend preliminary observations that a variant of HIV-2, which has the ability to infect a number of CD4 negative human cells, can utilize Fusin as an alternate receptor.